The pulsatile release of growth hormone from the pituitary somatotrops is regulated by two hypothalamic neuropeptides: growth hormone-releasing hormone and somatostatin. Growth hormone-releasing hormone stimulates the release of growth hormone whereas somatostatin inhibits the secretion of growth hormone. (Frohman et al., Endocrinology Review, (1986), 7:223-253 and Strobi et al., Pharmacol. Review, (1994), 46:1-34).
Release of growth hormone from the pituitary somatotrops can also be controlled by growth hormone-releasing peptides (GHRP). The hexapeptide GHRP, His-D-Trp-Ala-Trp-D-Phe-Lys-amide (GHRP-6), was found to release growth hormone from the somatotrops in a dose-dependent manner in several species including man (Bowers et al., Endocrinology, (1984), 114:1537-45). Subsequent chemical studies on GHRP-6 led to the identification of other potent growth hormone secretagogues such as GHRP-I, GHRP-2 and hexarelin (Cheng et al., Endocrinology, (1989), 124:2791-8; Bowers, C. Y., Novel GH-Releasing Peptides, Molecular and Clinical Advances in Pituitary Disorders, Ed: Melmed, S., Endocrine Research and Education, Inc., Los Angeles, Calif., USA, (1993), 153-7 and Deghenghi et al., Life Science, (1994), 54:1321-8). The structures of these three growth hormone secretagogues are as shown:
GHRP-IAla-His-D-(2′)-Nal-Ala-Trp-D-Phe-Lys-NH2; GHRP-2D-Ala-D-(2′)-Nal-Ala-Trp-D-Nal-Lys-NH2;and HexarelinHis-D-2-MeTrp-Ala-Trp-D-Phe-Lys-NH2.
GHRP-I, GHRP-2, GHRP-6, and hexarelin are synthetic growth hormone secretagogues (hereinafter collectively referred to as “GHS”). GHS stimulate the secretion of growth hormone by a mechanism different from that of growth hormone-releasing hormone (Bowers, C. Y. et al., Endocrinology, (1984), 114:1537-45; Cheng et al., Endocrinology, (1989), 124:2791-8; Bowers, C. Y., Novel GH-Releasing Peptides, Molecular and Clinical Advances in Pituitary Disorders, Ed: Melmed, S., Endocrine Research and Education, Inc., Los Angeles, Calif., USA, (1993), 153-7 and Deghenghi et al., Life Science, (1994), 54:1321-8).
The low oral bioavailability (generally accepted as <1%) of these peptidyl growth hormone secretagogues encouraged the search for non-peptide compounds mimicking the action of GHRP-6 in the pituitary. Several benzolactams and spiroindanes have been reported to stimulate growth hormone release in various animal species and in man (Smith et al., Science, (1993), 260:1640-3; Patchett et al., Proceedings of the National Academy Science USA, (1995), 92:7001-5; and Chen et al., Bioorganic Modern Chemistry Letter, (1996), 6:2163-9). A specific example of such a small spiroindane is MK-0677 (Patchett et al., Proceedings of the National Academy of Science, USA, (1995), 92:7001-5) which has the following structure:

The actions of the above-mentioned GHS (both peptide and non-peptide) appear to be mediated by a specific growth hormone secretagogue receptor (hereinafter referred to collectively as “GHS receptor”)(Howard et al., Science, (1996), 273:974-7 and Pong et al., Molecular Endocrinology, (1996), 10:57-61). The GHS receptor found in the pituitary and hypothalamus glands of various mammalian species (GHSR1a) is distinct from the growth hormone-releasing hormone receptor (hereinafter referred to as “GHRH receptor”). The GHS receptor was also detected in the other central nervous tissues and peripheral tissues such as the adrenal and thyroid glands, as well as heart, lung, kidney and skeletal muscle tissues (Chen et al., Bioorganic Medical Chemistry Letter, (1996), 6:2163-9; Howard et al., Science, (1996), 273:974-7; Pong et al., Molecular Endocrinology, (1996), 10:57-61; Guan et al., Molecular Brain Research, (1997), 48:23-9 and McKee et al., Genomics, (1997), 46:426-34). A truncated version of GHSR1a has also been reported. (Howard et al., Science, (1996), 273:974-7).
The GHS receptor is a G-protein coupled-receptor. Effects of GHS receptor activation include depolarization and inhibition of potassium channels, increase in intercellular concentrations of inositol triphosphate (IP3) and intracellular calcium concentrations, although transient for the latter (Pong et al., Molecular Endocrinology, (1996), 10:57-61; Guan et al., Molecular Brain Research, (1997), 48:23-9 and McKee et al., Genomics, (1997), 46:426-34).
Ghrelin is a naturally occurring peptide which is believed to be an endogenous ligand for the GHS receptor (Kojima et al., Nature, (1999), 402:656-60). The native structures of ghrelin from several mammalian and non-mammalian species are known (Kaiya et al., Journal of Biological Chemisty, (2001), 276:40441-8 and International Patent Application PCT/JP00/04907 [WO 01/07475]). A core region present in ghrelin was responsible for observed activity at the GHS receptor. The core region comprises the four N-terminal amino acids wherein the serine in the third position is normally modified with n-octanoic add. In addition to acylation by n-octanoic acid, native ghrelin may also be acylated with n-decanoic add (Kaiya et al., Journal of Biological Chemistry, (2001), 276:40441-8).
GHS molecules such as ghrelin and its analogs have a variety of different therapeutic (Inui, A., FASEB J., (2004), 18:439-56; Muller et al., Neurobiology of Aging, (2002), 23:907-19; Casanueva, F. F. et al., TEM, (1999), 10:30-8 and Ankerson, M. et al., DDT, (1999) 4:497-506) and diagnostic uses. Compounds exhibiting agonist effects at the GHS receptor were found to promote the stimulation of growth hormone secretion. As such, analogs of ghrelin are indicated for improving a growth hormone-deficient state (U.S. Pat. Nos. 6,861,409; 6,967,237 and Casanueva, F. F. et al., TEM, (1999), 10:30-8), increasing muscle mass (U.S. Pat. Nos. 6,861,409 and 6,967,237) and/or physical strength (Ankerson, M. et al., DDT (1999), 4:497-506), improving bone density (U.S. Pat. Nos. 6,861,409, 6,967,237 and 6,251,902 and Sibilia, V. et al., Growth Horm. IGF Res., (1999), 9:219-27), treating osteoporosis (WO 97/24369; WO 98/58947; Casanueva, F. F. et al., TEM, (1999), 10:30-8), overcoming male and female sexual dysfunction (U.S. Pat. No. 6,967,237; Casanueva, P. F. et al., TEM, (1999) 10:30-8), treating cardiovascular disease (WO 97/24369; WO 98/58947; U.S. Pat. No. 6,251,902; DeGennaro Colonna, V. et al., Eur. J. Pharmacol., (1997), 334:201-7 and Casanueva, F. F. et al., TEM, (1999), 10:30-8), relieving arthritis pain (Granado, M., AJP Endo., (2005), 288:486-92) and treating systemic lupus erythematosus or inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) (U.S. Patent Publication 2002/0013320). Agonistic analogs of ghrelin can facilitate a gain in body weight (U.S. Pat. No. 6,967,237; Tschop, M. et al., Endocrinology, (2002), 143:558-68) which in turn can be used to maintain a desired body weight (U.S. Pat. Nos. 6,861,409 and 6,967,237) and/or to recover physical function (U.S. Pat. Nos. 6,967,237 and 6,251,02 and WO 97/24369).
Ghrelin also increases appetite (U.S. Pat. No. 6,967,237 and Okada, K. et al., Endocrinology, (1996), 137:5155-8). As such, ghrelin is used to treat patients suffering from certain diseases or disorders or undertaking medicinal regimens which are traditionally accompanied with an undesirable weight loss. Such diseases and disorders include anorexia (U.S. Pat. No. 6,967,237; Tschop, M. et al., Endocrinology, (2002), 143:558-68), bulimia (U.S. Pat. No. 6,967,237), cachexia (U.S. Pat. Nos. 6,967,237 and 6,251,902) particularly cancer-induced cachexia (U.S. Pat. No. 6,967,237 and Tschop, M. et al., Endocrinology, (2002), 143:558-68), AIDS (U.S. Pat. Nos. 6,861,409 and 6,967,237; Tschop, M. et al., Endocrinology, (2002), 143:558-68), wasting syndrome in the frail and/or elderly (U.S. Pat. Nos. 6,861,409 and 6,967,237; WO 97/24369; Ankerson, M. et al., DDT, (1999), 4:497-506) and chronic renal failure (Casanueva, F. F. et al., TEM, (1999), 10:30-8). Medicinal treatments traditionally accompanied by a weight loss include chemotherapy, radiation therapy, temporary or permanent immobilization, and/or dialysis (U.S. Pat. Nos. 6,967,237 and 6,251,902).
Obesity is a major risk factor for diabetes and a large fraction of non-insulin-dependent diabetes mellitus (otherwise referred to as “NIDDM”) patients are obese. Both conditions are characterized by elevated circulating insulin levels and suppressed GH levels. GH treatment of GH-deficient adults Jorgensen, J. O. L., et al., Lancet, (1989), 1:1221), obese women (Richelsen, B., et al., Am J Physiol, (1994), 266:E211) and elderly men (Rudman, D., et al, Horm Res, (1991), 36 (Suppl 1):73) has been shown to produce increases in lean body, hepatic and muscle mass while decreasing fat mass. Accordingly, administration of a ghrelin agonist is an attractive therapy for obesity except for the diabetogenic effects of GH (U.S. Pat. No. 6,251,902; Ankerson, M. et al., DDT, (1999), 4:497-506 and Casanueva, F. F. et al., TEM, (1999), 10:30-8). Complications of diabetes such as retinopathy and/or for treating cardiovascular disorders (U.S. Pat. No. 6,967,237; U.S. Patent Application Publication 2003/0211967) may be indirectly treated by ghrelin as well.
Paradoxically, ghrelin antagonists can be used to facilitate weight loss in an obese individual wherein said obesity is not due to the onset of NIDDM (U.S. Pat. No. 6,967,237 and U.S. Patent Application Publication 2003/0211967) as well as several other identified indications. Compounds exhibiting antagonist effects at the GHS receptor to promote the suppression of growth hormone secretion, e.g., antagonist analogs of ghrelin, are indicated for the treatment excessive growth hormone secretion (U.S. Patent Application Publication 2002/0187938), to facilitate weight loss in the non-obese (U.S. Pat. No. 6,967,237), to maintain an ideal weight and to decrease appetite (U.S. Pat. No. 6,967,237). Excessive weight is a contributing factor to many diseases or conditions such as hypertension, dyslipidemia and cardiovascular disease (U.S. Patent Application Publication 2003/0211967 and U.S. Pat. No. 6,967,237) as well as gall stones, osteoarthritis (U.S. Pat. No. 6,967,237), certain cancers (U.S. Patent Application Publications 2003/0211967 and 2004/0157227 and U.S. Pat. No. 6,967,237) and Prader-Willi syndrome (U.S. Pat. No. 6,950,707). Use of ghrelin antagonists to facilitate weight loss, therefore, would be useful to reduce the likelihood of such diseases or conditions and/or comprise at least part of a treatment for such diseases or conditions.
Analogs of growth hormone secretagogues have also been employed to promote gastrointestinal motility, particularly in patients suffering from decreased gastrointestinal motility resulting from post-operative ileus or from gastroparesis incidental to the onset of diabetes or a chronic diabetic state (U.S. Pat. No. 6,548,501).
Given the wide variety of beneficial effects that growth hormone secretagogues have to offer, there is a need in the art for effective agonist or antagonist GHS molecules.